COPD is the third leading cause of death in the US. Development of novel therapies for COPD is currently hampered by lack of clinical tools to assess therapeutic responses. Magnetic resonance imaging (MRI) using hyperpolarized xenon-129 (Xe129) gas has emerged as a candidate to address this need. Recently, our research group developed a new Xe129 MRI technique that permits 3D regional mapping of both ventilation (airflow) and gas uptake (gas exchange) by tissue and blood in the human lung through a single breath hold acquisition (<11 seconds). To our knowledge, it is the first non-invasive imaging method to measure regional gas exchange - the primary function of the human lung. Our preliminary studies showed a high potential of this technique to detect diverse functional and pathological changes in the lungs with COPD. So the primary objective of this application is to test the ability of Xe129 MRI as a diagnostic tool to detect a response to curren mainstream therapeutics for COPD, and compare it with performances of existing clinical tools. And the secondary objective is to use high resolution computed tomography (HRCT) and pulmonary perfusion MRI to verify the abnormalities of lung functions detected by Xe129 MRI (gas uptake by lung tissue and blood), and thus indirectly validate this technique. The central hypothesis is that Xe129 MRI enables detection of physiologically relevant and clinically important pathologic changes found in the lungs of COPD subjects with unprecedented sensitivity, specificity and 3D resolution, which are not obtainable by standard clinical methods, thus, can be used to promote rapid development of novel therapeutics to benefit patients diagnosed with COPD. Guided by strong preliminary data, the central hypothesis will be tested by pursuing two Specific Aims: 1). Implement an image post-processing method to co-register images from Xe129 MRI, perfusion MRI and HRCT acquisitions, and subdivide them to individual lung lobes; 2). Perform a pilot study in 30 COPD patients (10 in each of GOLD stages 1-3) starting a combined inhaler, Advair, for a 90-day trial to assess the functional responses in the COPD lungs to treatment using Xe129 MRI, and investigate the correlation between Xe129 MRI, perfusion MRI and HRCT. Achieving Aim 1 will lay the foundation for quantitative analysis of the regional lung function and investigation of the correlations between different imaging acquisitions in Aim 2. Aim 2 will test the central hypothesis that Xe129 MRI can detect potential diagnostic gains obtained by considering regional effects of Advair in lungs with COPD, which is not obtainable by using existing clinical tools, and also validate the Xe129 MRI technique. The results of the project are expected to improve our understanding of the functional response of the lungs with COPD to current therapeutics, and provide evidence to consider Xe129 MRI as a diagnostic strategy to assess and monitor therapeutic responses of existing and new pharmaceuticals, and thus this technique can stimulate development of novel therapies for COPD in the future.